Trillions of microorganisms constitutively colonize the mammalian gastrointestinal (GI) tract and are essential to aid in nutrient metabolism and resistance to pathogen infection, as well as the development and maturation of the immune system. In the healthy intestine, most commensal bacteria are restricted to the lumen of the GI tract or found associated with the surface of the intestinal epithelium and remain physically separated from the immune cells that populate the lamina propria and intestinal-associated lymphoid tissues including isolated lymphoid follicles (ILF), Peyer's patches (PP) and the mesenteric lymph nodes (mLN) (Chow et al., 2010, Advances in immunology 107, 243-274; Hooper et al., 2012, Science 336, 1268-1273; Hooper and Macpherson, 2010, Nat Rev Immunol 10, 159-169). Physical separation of commensal bacteria from immune cells is achieved by multiple physical and biochemical mechanisms that include epithelial cells that line the intestine, tight junction proteins, and secretion of anti-microbial peptides, mucus and immunoglobulin A (Chow et al., 2010, Advances in immunology 107, 243-274; Hooper et al., 2012, Science 336, 1268-1273; Hooper et al., 2010, Nat Rev Immunol 10, 159-169). Anatomical segregation of commensal bacteria from the immune system, often referred to as the “demilitarized zone”, is essential to prevent pathologic immune responses against commensal bacteria. Consistent with this, translocation of commensal bacteria across the intestinal epithelium can lead to the generation of pro-inflammatory immune cell responses and are often associated with the pathogenesis of multiple chronic diseases, such as inflammatory bowel disease, metabolic disorders and HIV/AIDS (Brenchley et al., 2012, Annual review of immunology 30, 149-173; Manichanh et al., 2012, Nature reviews, Gastroenterology & hepatology 9, 599-608).
Recent studies suggest that a unique subset of commensal bacteria can colonize the interior of intestinal-associated lymphoid tissues of healthy mammals (Fung et al., 2014, Immunological reviews 260, 35-49; Kunisawa et al., 2012, Frontiers in immunology 3, 65; Obata et al., 2010, Proceedings of the National Academy of Sciences of the United States of America 107, 7419-7424; Sonnenberg et al., 2012, Science 336, 1321-1325). Using 16S rDNA sequencing and fluorescence in situ hybridization (FISH), one report identified the presence of multiple species of commensal bacteria in the interior of ILFs, PPs and the mLN of healthy mice, non-human primates and humans (Obata et al., 2010, Proceedings of the National Academy of Sciences of the United States of America 107, 7419-7424). These bacteria include Alcaligenes spp., Achromobacter spp., Bordetella spp. and Ochrobactrum spp. 16S rDNA for many of these lymphoid tissue-resident commensal bacteria (LRCs) were found associated with CD11c+ dendritic cells (DCs), suggesting a role for DCs in lymphoid tissue colonization. In a subsequent study, it was demonstrated that interleukin (IL)-22 and group 3 innate lymphoid cells (ILC3) are important in preventing systemic dissemination of one LRC, Alcaligenes xylosoxidans, and subsequent induction of systemic inflammation (Sonnenberg et al., 2012, Science 336, 1321-1325). These data highlight that intestinal-associated lymphoid tissues are potential sites for colonization by commensal bacteria and innate immune pathways maintain anatomical containment between LRCs and the systemic immune system. However, the functional significance of this colonization to the host remain undefined.